PROJECT SUMMARY (Core C - Gene Expression Signatures) HIV has proven its ability to defeat all vaccine candidates tested to date. However, evidence in humans and model systems demonstrates that immune system is capable of generating antibodies that neutralize multiple HIV-1 viral strains. While the mechanisms that lead to the generation of broadly neutralizing antibodies remain to be determined, a number of studies have shown that the early innate immune responses to vaccines are predictive of the subsequent adaptive response which is responsible for protection. Thus, transcriptional signatures of innate responses can be used to discover gene regulatory networks, or ?rules?, driving adaptive responses and vaccine efficacy. In this program we seek to comprehensively evaluate, and compare 4 novel vaccines that deliver a common HIV immunogen, but differ in their mode of delivery and their potential immunostimulatory profiles. We will use early transcriptional signatures (gene signatures) as part of this program to reveal the innate immune networks elicited by each vaccine candidate and delivery strategy, to correlate vaccine elicited immunogenicity with early innate immune signatures, to provide a framework for predicting the efficacy of vaccine candidates, and to lay a foundation for future rational vaccine designed to activate desired innate immune responses and subsequent adaptive responses.